The Role of VEGF-C and VEGF-D in Coronary Artery Disease: From Molecular Pathophysiology to Therapeutic Lymphangiogenesis.

Traditional therapeutic strategies for coronary artery disease (CAD) primarily focus on arterial perfusion, largely overlooking the critical role of the cardiac lymphatic system in maintaining myocardial fluid, lipid, and immune homeostasis. The vascular endothelial growth factor C (VEGF-C) and VEGF-D/VEGF receptor-3 (VEGFR3) signaling axes are the primary drivers of lymphangiogenesis. However, recent clinical and mechanistic insights suggest that these two homologous ligands exert highly distinct and divergent pathophysiological roles under ischemic stress. This review synthesizes the current clinical, epidemiological, and preclinical evidence evaluating the distinct temporal and spatial dynamics of the VEGF-C/D axis. Large-scale clinical cohorts have revealed a striking prognostic divergence: while elevated circulating VEGF-D levels independently predict incident heart failure, atrial fibrillation, and mortality, low serum VEGF-C levels independently predict mortality. Mechanistically, adventitial lymphatics actively govern scavenger receptor class B type I (SR-BI)-dependent reverse cholesterol transport and macrophage trafficking. Preclinical large animal validation and phase 1/2 clinical trials (such as KAT301 and ReGenHeart) have demonstrated that timely, localized pro-lymphangiogenic interventions-leveraging modified mRNA, lipid nanoparticles, or sequential growth factor delivery kinetics-effectively resolve myocardial edema, suppress adverse remodeling, and improve the myocardial perfusion reserve. In conclusion, VEGF-C and VEGF-D represent a complex molecular dualism in CAD. Transitioning from non-specific growth factor overproduction to cell-specific, sequentially timed lymphatic therapeutics is a new frontier in halting the progression of adverse ventricular remodeling and chronic heart failure.